Prostaglandin E.sub.2 (abbreviated as PGE.sub.2 hereinafter) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE.sub.2 has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect of digestive peristalsis, an awakening effect, a suppressive effect of gastric acid secretion, hypotensive activity and diuretic activity etc.
In the recent study, it was found that PGE.sub.2 receptor was divided into some subtypes which possess different physiological roles each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors investigated to find new compounds which bind on each receptor specifically, so that we found that the compounds of the present invention could bind strongly on EP2 subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I), possess a strong binding activity on EP2 subtype receptor. Therefore, they are useful for prevention and/or treatment of immunological diseases (autoimmune diseases, organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, hepatopathy, abortion, premature birth or retina neuropathy of glaucoma etc.
Among the compounds of the present invention of formula (I), compounds which bind weakly on receptor subtypes except EP2 receptor and on other receptors for arachidonic acid cascade metabolites (thromboxane receptor, PGI.sub.2 receptor etc.) do not express other effects and therefore, it is probable that these compounds will be medical agents which have less side-effects.
On the other hand, many patent applications of PG derivatives are known. The following application is mentioned for example.
In the specification of JP54-115351 (i.e. U.S. Pat. No. 4,275,224), a compound of formula (A) ##STR3##
[wherein R.sup.1A and R.sup.2A are hydrogen; R.sup.3A is hydrogen or is taken together with R.sup.4A to form a methylene chain of 4 carbon atoms wherein a cycloalkyl of 6 carbon atoms inclusive is formed, or is taken together with R.sup.4A to form a bicycloalkenyl or bicycloalkyl moiety having the formula ##STR4##
(wherein pA is an integer having a value of from 0 to 1 and qA is an integer having a value of from 2 to 3 and wherein the double bond of such bicycloalkenyl is in the qA bridge); R.sup.4A together with R.sup.3A forms a cycloalkyl, bicycloalkyl or bicycloalkenyl as defined above, or together with R.sup.5A forms a methylene chain of 3 carbon atoms wherein a cycloalkyl of 4 carbon atoms inclusive is formed; R.sup.5A is hydrogen, or is taken together with R to form a cycloalkyl as defined above; and R.sup.6A is hydrogen or straight-chain alkyl having 8 carbon atoms.]
are disclosed as having prostaglandin-like activity.